Patent Revoked for Lack of Sufficiency in View of Post-Published Data from Phase III Clinical Trial

The Board of Appeal in T 0816/22 considered whether Phase III clinical trial data, which was only made publicly available after the filing date, could be used to establish lack of sufficiency for a second medical use patent.

Second medical use

The patent in question, EP 3071219, related to a C1-esterase inhibitor (C1-INH) for treating antibody-mediated rejection (AMR) in kidney transplant patients. This rejection type occurs as some patients are “sensitised” to the donor organ because of a pre-existing antibody which may have resulted from a previous organ donation, blood transfusion or pregnancy. C1-INH was previously known as a valid treatment for acute hereditary angioedema (HAE) attacks.

Sufficiency

The application must disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art (Article 83 EPC). This does not necessarily require the provision of data to the level of a clinical trial; pre-clinical data may be enough. For a medical use claim, the skilled person, with the teaching of the patent in hand and applying common general knowledge, must be able to achieve the therapeutic effect recited in the claim.

The Opposition Division had considered that the granted patent met the requirement of Article 83 EPC.  The Board of Appeal started from the assumption that the Opposition Division’s assessment that the patent as granted was plausible was correct, as at the time of filing the skilled person would have been able to affect a therapeutic effect on AMR using the disclosure of the patent.

Data from the Clinical Trials

The application disclosed methods of treating antibody-mediated rejection (AMR) in kidney transplant patients with the C1-INH formulation named Cinryze® at a dose of 5,000-20,000 units given in divided doses over 10-20 days. The application as filed contained Phase II data relating to the treatment of glomerulopathy. Glomerulopathy involves inflammation and damage to the filtering part of the kidneys, resulting in toxins, metabolic waste and excess fluid not being correctly filtered and remaining in the body. It is a widely accepted manifestation of AMR.

The Phase II data showed that Cinryze® reduced chronic glomerulopathy in patients compared to a placebo. The Phase II trial data was compelling enough to warrant continuation of the drug trial, with the drug entering Phase III with a larger cohort of patients.

The Phase III trial for Cinryze® used the same dosage regimen as in the patent in a larger cohort of patients. However it showed no difference in transplant glomerulopathy between C1-INH and placebo groups.

Outcome

The study was terminated after 36 months because "[f]ollowing a prescheduled interim analysis performed by the DMC, it was determined that the study met the pre-specified criteria for futility". The patent proprietor argued that the term “futility” was only used in a regulatory context, and should not tied to the “futility” of a technical effect in the sense of Article 83 EPC.

The patent proprietor argued that as the termination of the study was a commercial decision, it did not indicate that there were no therapeutic effects. However, the only data point taken and analysed from this time period was after 6 months of treatment. The 6 month endpoint data produced was a binary endpoint of "Percentage of Subjects With New or Worsening Transplant Glomerulopathy (TG) at Month 6 Post-Treatment" and reported 47.5% patients in the placebo group and 50% patients in the Cinryze® group. The patent proprietor argued that a longer patient follow up period may have demonstrated the desired beneficial effects, as no secondary endpoints were analysed or reported, aside from this 6 month data point.

The Board of Appeal noted that “therapy is not limited to completely curing a disease or condition, but also includes alleviating, removing or lessening the symptoms of any disorder or malfunction of the human or animal body.” but ultimately concluded that there was complete absence of any therapeutic effect with the claimed dosage regimen. In the post-published data “For the very parameter that was considered ‘a clinical marker of AMR in a transplant patient' in the patent...[the post-published evidence] found no effect for a larger patient cohort”.

The Board of Appeal determined from the basis of the Phase III data that the patent did not disclose the claimed invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art (Article 83 EPC). The patent was revoked.

This decision illustrates that the sufficiency of a second medical use patent may be vulnerable if it can be argued that post-published data establishes that there is no therapeutic efficacy.